Na plus K ions-ATPase in the cardiac cytoplasmic membrane is essential for the generation and maintenance of transmembrane electro- chemical gradients and hence for the maintenance of excitability of cardiac cells. The consequences of the inhibition or stimulation of this enzyme system on the function of heart are not understood. Cardiac glycosides have been demonstrated to inhibit cardiac Na plus K ions- ATPase activity and simultaneously increase the contractile force. The causal relationship between these two phenomena is yet to be extensively explored. The objective is to determine whether a causal relationship exists between the inhibition of cardiac Na plus K ions-ATPase by cardiac glycosides and the inotropic and/or toxic effects of these drugs. This will be achieved by studying the relationship between cation pump inhibition (as monitored by ouabain-sensitive Rb86 transport) and inotropic response in isolated heart preparations during the development and dissipation of the inotropic response to various glycosides as well as with different areas of the heart which may have different sensitivities to cardiac glycosides. Further, the relationship between cation pump inhibition or stimulation and cardiac contractile force will be studied using isolated heart preparations and agents or factors that affect Na plus K ions-ATPase activity other than cardiac glycosides. The consequences of cation pump inhibition which leads to the positive inotropic and/or toxic responses will be studied in order to understand the molecular mechanism of action of cardiac glycosides. The nature of the molecular interaction between the cardiac glycosides and their inotropic and/or toxic "receptor" and factors which influence this interaction will also be studied using cardiac Na plus K ions-ATPase as the molecular model for the receptor. Finally, the implication of brain Na plus K ions-ATPase inhibition in the genesis of glycoside arrhythmias will be explored.